The invention relates to a process for preparing compounds of the formula I 
where R1 is
a linear or branched alkyl radical having from 1 to 10 carbon atoms, in which one or two CH2 groups may be replaced by xe2x80x94CHxe2x95x90CH groups or
a cycloalkyl radical or cycloalkylalkylene radical having from 5 to 12 carbon atoms or
a phenyl radical or phenylmethyl radical
and said radicals are monosubstituted by xe2x80x94COOH, xe2x80x94COOA, xe2x80x94CONH2, xe2x80x94CONHA, xe2x80x94CON(A)2 or xe2x80x94CN where A is an alkyl group having from 1 to 6 carbon atoms.
Compounds of the formula I constitute an effective starting point for the synthesis of medicaments,since the presence of the carbonyl group of pyrimidine makes it possible to attach various radicals, thereby paving the way for the synthesis of novel medicinal substances whose properties may be modified by varying the group to be attached.
Medicinal substances containing the heterocyclic system of compounds of the formula I are described, for example, in DE-198 190 23 A1. These compounds and the salts thereof show good tolerability and possess very valuable pharmacological properties. They show in particular a specific inhibition of cGMP phosphodiesterase (PDE V). Therefore the compounds are suitable for the treatment of diseases of the cardiovascular system, in particular heart failure, and for the treatment and/or therapy of impaired potency (erectile dysfunction).
For broad application of these medicinal substances it is necessary to be able to provide sufficient amounts of suitable starting compounds. The medicinal substances should be obtained in great purity because of the rigorous demands on their purity. Furthermore the reaction should result in a high yield in order to keep costs down and to avoid waste disposal problems.
Houben-Weyl, E9b/2, page 29 to 30 describes the preparation of 2-substituted quinazolin-4(3H)-ones. In this process anthranilic acid or anthranilic esters are reacted with nitrites.
In J. Heterocyclic Chem. 17, 1497 (1980) K. G. Dave et al. describe a process for preparing condensed pyrimidines. The synthesis of benzothieno[3,2-d]pyrimidines and of substituted 4-ethoxy-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidines is described inter alia.
The object of the invention is to provide a process for preparing compounds of the formula I which is simple to carry out and provides the compounds of the formula I in good yields and high purity.
This object is achieved by a process for preparing compounds of the formula I wherein a 2-aminobenzothiophene-3-carboxylic ester of the formula II 
where R2 is a linear or branched alkyl group having from 1 to 6 carbon atoms, in particular methyl, and a nitrile of the formula III
Nxe2x89xa1Cxe2x80x94R1 xe2x80x83xe2x80x83III 
where R1 has the above meaning in solution or suspension in a solvent is reacted in the presence of an acid.
Preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl is used as radical R2 of the carboxylic ester of the formula II. For the radical R1 of the nitrile of the formula III linear or branched alkyl radicals having from 1 to 10 carbon atoms may be used, in which one or two CH2 groups may be replaced by xe2x80x94CHxe2x95x90CHxe2x80x94 groups. The alkyl radical used is preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-3-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, linear or branched heptyl, octyl, nonyl or decyl. Furthermore R1 may be but-2-enyl or hex-3-enyl.
Cycloalkyl radicals or cycloalkylalkylene radicals having from 5 to 12 carbon atoms which may be used are cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene. The cycloalkyl radicals preferably comprise from 5 to 7 carbon atoms. Examples are cyclopentyl, cyclohexyl or cycloheptyl groups. Furthermore R1 may be a phenyl or phenylmethyl radical.
Each of said radicals is mono-substituted by xe2x80x94COOH, xe2x80x94COOA, xe2x80x94CONH2, xe2x80x94CONHA, xe2x80x94CON(A)2 or xe2x80x94CN. A is in this case alkyl having from 1 to 6 carbon atoms. Examples of suitable groups are methyl, ethyl or propyl, and isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, neopentyl, isopentyl or hexyl.
In the process according to the invention the compounds of the formula I are obtained as salts. These precipitate in general from the reaction solution as a crystalline precipitate and may be obtained in sufficient purity by simple filtering off.
The synthesis of the compound of the formula I is in general carried out by initially introducing the carboxylic ester of the formula II and the nitrile of the formula III into a suitable solvent and then adding the acid, for example by passing it into the solution as a gas.
However, it is possible to significantly increase the reaction yield and the purity of the reaction product of the formula I and further to shorten the reaction time if initially an excess of acid is dissolved in the solvent, preferably the solvent is saturated with the acid, and subsequently the 2-aminobenzothiophene-3-carboxylic ester of the formula II and the nitrile of the formula III are added.
An excess of acid is an amount of acid so large that after quantitative reaction of the compounds of the formulae I and II and subsequent precipitation as salt unbound acid still remains in the solution. This amount of acid is to be already present in the reaction mixture at the start of the reaction.
The reaction may proceed such that first a, preferably saturated, solution of the acid in the solvent is prepared and separately therefrom a solution which contains the compounds of the formula I and the formula II. It is possible either for the two solutions then to be introduced simultaneously into a reaction vessel for the reaction or for the acid solution to be initially charged and the solution of the compounds of the formula I and the formula II to be added. It is, however, also possible to initially charge the solution of the compounds of the formula I and the formula II and to add the acid solution. However, in this case the acid solution should be added very rapidly to the solution of the compounds of the formula I and the formula II.
It has proved to be appropriate for the solvent to be selected from the group consisting of ethers, alcohols, esters, water, formamides, amines, carboxylic acids, chlorinated hydrocarbons and mixtures thereof. A particularly suitable solvent is dioxane.
Suitable ethers are, for example, diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane. Suitable alcohols are, for example, methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol. Also suitable are glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methylglycol or ethylglycol), diethylene glycol dimethyl ether (diglyme). Suitable amides are, for example, acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide. A suitable carboxylic acid is, for example, glacial acetic acid. An ester which may be used is, for example, ethyl acetate. Suitable chlorinated hydrocarbons are, for example, trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane. It is also possible to employ mixtures of the solvents mentioned.
The acids are suitably selected from the group consisting of Brxc3x6nsted acids and Lewis acids, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, aluminium trichloride and boron trifluoride. Particularly suitable are gaseous acids, in particular hydrogen chloride.
The reaction is suitably carried out at a temperature of from xe2x88x9210xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 60xc2x0 C., in particular 10xc2x0 C. to 50xc2x0 C.
In a particularly preferred embodiment of the process according to the invention the addition of acid to the mixture is continued during the reaction. Thus it is possible to achieve nearly quantitative precipitation of the compound of the formula I as salt of the acid.
The compounds of the formula I constitute a valuable starting substance for further syntheses. It is possible to achieve further activation of the compound of the formula I, if in a further step the compound of the formula I is converted into a compound of the formula IV 
by a chlorinating agent. The chlorine may simply be substituted by appropriate nucleophiles.
The chlorinating agent is suitably selected from the group consisting of SOCl2, POCl3, PCl5, ClCOCOCl.
The compounds of the formulae II and III are either known or may be prepared by the skilled worker using known synthesis pathways. An example of a synthesis of the compounds of the formulae II and III is described in the following with particularly preferred compounds. For other radicals R1 and R2 the reactions can be carried out analogously.
Synthesis of methyl 2-aminobenzothiophene-3-carboxylate 7 starts from thiosalicylic acid 1. The carboxyl group is reduced by lithium aluminium hydride resulting in the alcohol 2. Afterwards the thiol group is reacted with benzyl chloride to give the thioether 3. Next the hydroxyl group of the compound 3 is reacted with hydrochloric acid to give the chloride 4 which is then reacted with sodium cyanide to give the nitrile 5. This is reacted with dimethyl carbonate to give the compound 6 which is finally cyclized to give the compound 7. 
Synthesis of the preferred methyl trans-4-cyanocyclohexanecarboxylate starts from methyl trans-cyclohexane-1,4-dicarboxylate 8 which is first hydrolysed by KOH to give the monomethyl ester 9. This is first converted into the acid chloride by thionyl chloride and then into the acid amide 10 by ammonia. The nitrile 11 is finally obtained from the acid amide 10. 
According to the invention, the compounds 7 and 11 are cyclized to the imidone 12. By reaction with thionyl chloride it is possible to obtain the compound 13 the chlorine group of which may be nucleophilically substituted and which thus is available as a starting compound for the synthesis of a plurality of pharmacologically active substances. 
In the following, the invention is illustrated by examples.